At least three subreceptors of the opioid receptorial system are known: mu (μ), delta (δ) and kappa (k) opioidergic receptors. The presence of epsilon (ε) opioid receptors has also been reported (K. J. Chang et al. in Molecular Pharmacology 26 (1984) 484-488). As regards the delta opioid receptors, the presence of two distinct subreceptors δ1 and δ2 has been described (D. F. Pacheco et al. Life Sciences 78 (2005) 54-60).
Diazabicyclic and diazatricyclic compounds having affinity for the opioidergic receptors are known in the art.
In patent application US 2003/195,217 3,9-diazabicyclo[3.3.1]nonane compounds are described, having formula (A1):
wherein R1 and R2, different from each other, are a C2-C8 acyl or group of formula (A1a) or of formula (A1b):—CH2—CH═C(B)Ra  (A1a)—CH2—CH2—CH(B)Ra  (A1b)wherein:    B has the meaning of:            C6-C10 aryl optionally substituted with the following G1 groups: C1-C3 alkoxy, C1-C2 haloalkyl, C1-C3 alkyl, halogen, CONHRb, COOH, cyano, nitro,        C5-C7 cycloalkyl group or an aromatic heterocyclo having 5 or 6 atoms, optionally benzocondensed, comprising at least one heteroatom selected from nitrogen, oxygen, sulphur, the heterocycle being optionally substituted with G1 groups herein above defined,            Ra has the meaning of hydrogen, C1-C4 alkyl, C5-C7 cycloalkyl or phenyl, optionally substituted with G1 groups.The compounds of formula (A1) have a central analgesic activity mediated by the opioidergic receptors comparable to that induced by morphine, but with the advantage of lower side effects.The compounds of formula (A1) has also been dealt with in the paper of G. A. Pinna et al., Bioorganic & Medicinal Chemistry, 10 (2002) 1929-1937, wherein the effect of various substituents of the bicyclic structure on the affinity towards opioidergic receptors is pointed out. It is therein shown that both the compounds of the examples of the patent application US 2003/195,217 and those described by G. A. Pinna et al. show a high or good affinity for the μ receptors and a poor or no affinity for the delta receptors.
U.S. Pat. No. 5,672,601 describes 3,8-diaza bicyclo[3.2.1]octane compounds and the corresponding pharmaceutical dosage forms having central analgesic activity mediated by the μ opioidergic receptors. The compounds are shown to be selective towards the μ receptors, with affinity similar to that of the morphine. The compounds have formula (A2):
wherein R3 and R4, different from each other, are C2-C8 acyl group or a group of formula —CH2-A-D wherein:    A is —CH2—CH2—, —CH═CH—, or —CH2—C(O)—,    D is selected from the following groups:    C6-C10 aryl, optionally substituted with the following G2 groups: CONHR3, COOH, ciano, nitro, NHCOR3,    aromatic heterocycle or an alicyclic group with a 5 or 6 atom ring, optionally benzocondensed, comprising at least one heteroatom selected from nitrogen, oxygen, sulphur, said heterocycles being optionally substituted with G2 groups.
Patent application WO 2005/108,402 relates to 3,6 diazabicyclo[3.1.1]heptane derivatives of formula (A3):
wherein R5 and R6, different from each other, are C2-C8 acyl or a group selected from the following formulas (A3a), (A3b), (A3c):—CH2—CH═C(B1)Rc  (A3a)—CH2—CH2—CH(B1)Rc  (A3b)—CH2—CH2—C(O)B1  (A3c)wherein:    B1 is selected from the following groups:            C6-C10 aryl, optionally substituted with the following G3 groups: C1-C3 alkoxy, C1-C2 haloalkyl, C1-C3 alkyl, halogen, COOH, cyano, nitro, CONHRd wherein Rd is a C1-C4 alkyl group,        C5-C7 cycloalkyl group,        an aromatic heterocycle having a ring with 5 or 6 atoms, optionally benzocondensed, containing at least one heteroatom selected from nitrogen, oxygen, sulphur, said heterocycle being optionally substituted with G3 groups,            Rc has the meaning of hydrogen, C1-C4 alkyl, C5-C7 cycloalkyl or phenyl, optionally substituted with G3 groups as herein above defined.The compounds show central analgesic activity mediated by the μ opioid receptors.
Another class of diazabicyclic compounds having affinity towards the opioidergic receptors is described in U.S. Pat. No. 7,358,243. In particular, this class of compounds is formed of diazabicyclo nonanes and decanes characterized by high affinity for the μ receptors and having general formula (A4):
wherein Q is —CH2—CH2— or —CH2—CH2—CH2— and one between R7 and R8 is —CH2—CH2—CH2—Re or —CH2—CH═CH—Re or —CH2—C≡C—Re, Re being aryl or heteroaryl and the other between R7 and R8 is —C(O)Rf, Rf being alkyl, or cycloalkyl, or cycloalkylalkyl, or aryl or arylalkyl.
U.S. Pat. No. 6,127,362 discloses 9,10-diazatricyclo-[4,4,1,12,5]-decane compounds and 2,7-diazatricyclo[4,4,0,03,8]decane compounds having analgesic activity, of formula (A5) or (A6):
wherein R9 and R10 are both hydrogen, or are different from each other and they are selected from:    hydrogen, C1-C8 alkyl, C2-C10 acyl,    a group Ar selected from:            phenyl optionally substituted,        naphthyl optionally substituted,        heterocyclic group having from 5 to 7 atoms in the ring, containing from 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, optionally the heterocyclic group is benzocondensed and is optionally substituted on the benzene ring,            a group of formula —CH2—CH═CH—Ar, wherein Ar is as defined above.The analgesic activity of the compounds of formula (A5) or (A6) is mediated by the μ opioid receptors, as it results from the affinity and selectivity values of the compounds described in the articles by G. A. Pinna et al., Bioorganic & Medicinal Chemistry, 11 (2003) 4015-4026, and by P. Vianello et al., Journal of Medicinal Chemistry, 43 (2000) 2115-2123.
Compounds having affinity and selectivity for the delta opioidergic receptors having a non peptidic structure are known in the art.
Morphine derivatives selective for the delta opioid receptors are described in WO 02/30,935 and have formula (A7):
wherein R11, R12, R13 and R14 have various meanings as reported in the patent application.
Agonist compounds selective of the delta opioid receptors are described in patent application US 2008/0096,925, and have the following formula (A8):
wherein R15, R16, R17, R18, R19, X, Y, Z, p have the various meanings therein reported.
Ligands of the delta opioid receptors are described in patent application US 2006/0148,850 having formula (A9):
wherein R20, R21, R22, R23, R24 have the various meanings reported therein.
Patent applications US 2006/0135,522 and US 2006/0135,763 disclose compounds modulating the delta opioid receptors having formulas (A10) and (A11) respectively:
wherein R25, R26, R27, R28, R29, R30, R31, R32, T, G, V, Q have the various meanings reported in said patent applications.
Other known compounds with affinity and selectivity for the delta opioid receptors are the BW373U86 and SNC80 derivatives described, respectively, by K. J. Chang et al. in J.P.E.T. 267 (1993) 852-857 and by S. N. Calderon et al. in J. Med. Chem. 37 (1994) 2125-2128. The structures of the two compounds are:

The above mentioned patents and patent applications describing the diazabicyclic and diazatricyclic compounds with affinity for the opioidergic receptors disclose the use of said compounds for the pain treatment.
The above mentioned U.S. Pat. No. 7,358,243 indicates that the opioidergic compounds, besides the use for the treatment of different kinds of pain (post-surgery pain, chronic pain such as neuropathic pain), can be used for the therapeutic treatment of other diseases and disorders such as allergic dermatitis, sexual disfunctions, alcoholism, nausea, vomit, depression, tabagism, obesity and disorders related to food intake, use of abuse substances (for example heroin, cocaine), spinal lesions, cerebral trauma, shock, stroke, gastrointestinal disorders. Eur. J. Pharmacol. 296 (1996) 199-207 reports the antiproliferative activity of agonist compounds of the opioidergic receptors on a human cell line of breast cancer. The article therefore makes it known the antitumoral activity of said agonist compounds. In the following articles: Veterinary Ophthalmology (2003) 6, 1, 73-76; Exp. Eye Res. 2007 January 84 (1) 185-190; British Journal of Anaesthesia 1998, 81 606-607, the capability of agonist compounds of the opioidergic receptors of reducing the intraocular pressure and thus the use of said compounds for eye pathologies, such as glaucoma, is shown. In the article published in Neuropeptides 33 (5) (1999) 360-368, the effect of compounds modulating the opioidergic receptors on food intake is reported, in particular it is indicated that agonists and antagonists of the opioidergic receptors are capable to increase or decrease the food intake respectively.
Patent application WO 06/113,468 describes the use of compounds modulating the opioidergic receptors for the treatment of arthritis, psoriasis, asthma, cardiac disorders, sexual disfunctions, pain, incontinence and urogenital tract disorders.
Patent application US 2005/203,123 relates to antagonist compounds of the opioidergic receptors and their use for the treatment of gastrointestinal disorders, pain, obesity, Alzheimer and Parkinson diseases and related disorders. The use of opioidergic compounds for the treatment of diabetes and atherosclerosis is described in patent applications WO 05/092,836 and WO 05/066,164.
Patent application WO 04/089,372 describes the use of compounds which modulate the opioidergic receptors for the treatment or prevention of the central nervous system disorders such as anxiety and depression. The antidepressant and relaxing effects of the compound (+)-4-[(aR)-a-((2S,5R)-4-allil-2,5-dimethylpiperazinyl)-3-methoxy-benzyl]-N,N-diethylbenzamide, called SNC80, selective agonist of the delta opioidergic receptors, are reported in Journal of Pharmacological Sciences 95 (2004) 374-380.
Patent application WO 04/060,321 relates to therapeutic compositions comprising agonists of the opioidergic receptors having cardioprotective effects.
Patent applications WO 02/42,309 and WO 01/46,198 describe that opioidergic compounds can be used also as immunostimulants or immunosuppressants.
U.S. Pat. No. 5,780,589 reports the activity of the ligands of the opioid receptors in analgesia, in the modification of the peptide hormone secretion, in the body temperature modulation, in the respiratory depression, in the gastrointestinal functions, in the immune system activity. The patent describes also the use of opioids in the therapeutic treatment of the following pathologies: abuse of alcohol or opiates, neurologic diseases, hormonal disorders, disorders in the neurotransmitter release, neurologic disorders, immune system disfunctions, transplant rejection, pain, shock and cerebral lesions. This patent describes furthermore a new class of selective compounds for the delta opioid receptors having a peptide structure formed of dipeptides, tripeptides and cyclic peptides containing 2′,6′-dimethyl-L-tyrosine (Dmt) and 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic).
Patent application US 2003/0186,872 describes the use of agonist compounds of the delta opioid receptors for the treatment of sexual disfunctions and in particular for the treatment of the early ejaculation in men.
C. J. Kotzer et al. in J.P.E.T. 292 (2000) 803-809 describe the anticough properties of the delta opioid agonists. In particular the agonist of the delta opioids studied in this reference is the compound called SB 227122 (page 804).
The therapeutic use of compounds having affinity for the μ opioid receptors, as well known from the prior art, can involve undesired effects such as constipation, respiratory depression, motion disturbances, nausea, vomit, sedation, tolerance and dependence. It is furthermore known that the entity of said side effects is lower or even nullified in the case of use of compounds having affinity and selectivity for the delta opioid receptors (G. Dondio et al. J. Med. Chem. 40 (1997) 3192-3198). Recent studies point out the role of the delta opioid receptors in modulating the μ opioid receptors (R. Rozenfeld et al. The Scientific World Journal 7 (S2) (2007) 64-73; I. Gomes et al. PNAS 101 (2004) 5135-5139). Ligands of the delta opioid receptors are capable of modulating the analgesic effect of opioidergic agonists acting prevailingly through the μ opioid receptors, such as morphine, but reducing the effects thereof of the pharmacological dependence and tolerance, (E. E. Abdelhamid et al. J.P.E.T. 258 (1991) 299-303).